Tetrahydropyranyl-dihydro-pge1

ABSTRACT

4,5-DISUBSTITUTED - 3 - HYDROXYCYCLOPENTANONES (I) ARE PREPARED BY HYDROGENOLYZING THE CORRESPONDING 4,5-DISUBSTITUTED-2,3-EPOXYCYCLOPENTANONE (IV) WHICH IN TURN IS PROVIDED BY REACTING THE CORRESPONDING 4,5 - DISUBSTITUTED-2-CYCLOPENTEN-1-ONE (III) WITH ALKALINE HYDROGEN PEROXIDE. COMPOUNDS (III) ARE PREPARED BY CYCLIZING THE CORRESPONDING 2,3-DISUBSTITUTED LEVULINALDEHYDE (II) WITH A BASE. THE PRODUCTS OF THE PROCESS ARE BIOLOGICALLY ACTIVE, ESPEICALLY COMPOUND (I) SUBSTITUTED IN THE 4-POSITION WITH 3&#39;&#39;:HYDROXYOCTYL AND IN THE 5-POSITION WITH 6&#39;&#39;CARBOXYHEXYL. THIS COMPOUND HAS PROSTAGLANDIN-LIKE ACTIVITY, ESPECIALLY BLOOD PRESSURE LOWERING AND BROCHODILATOR ACTIVITY, AND IS A TOTALLY-SYNTHETIC DIHYDROPROSTAGLANDIN E1(DIHYDRO PGE1). THE PROCESSES OF THE INVENTION MAY ALSO BE USED TO OBTAIN COMPOUNDS WITH PROSTAGLANDIN-LIKE ACTIVITY FROM APPROPRIATELY SUBSTITUTED NATURALLY OCCURRING CYCLOPENTANONES, E.G. THOSE ISOLATED FROM THE CARIBBEAN GORGONIAN, PLEXAURA HOMOMALLA.

United States Patent 3,749,741 TETRAHYDR0PYRANYL-DIHYDR0-PGE Donald P.Strike, Rosemont, and Herchel Smith, Bryn Mawr, Pa., assignors toAmerican Home Products Corporation, New York, NY.

N 0 Drawing. Application Nov. 12, 1969, Ser. No. 876,116, which is acontinuation-in-part of application Ser. No. 765,020, Oct. 4, 1968,which in turn is a continuationin-part of application'Ser. No. 702,185,Feb. 1, 1968, all now abandoned. Divided and this application Apr. 15,1971, Ser. No. 134,467

Int. Cl. C07d 7/04 U.S. Cl. 260-345.7 1 Claim ABSTRACT OF THE DISCLOSURE4,5-disubstituted 3 hydroxycyclopentanones (I) are prepared byhydrogenolyzing the corresponding4,5-disubstituted-2,3-epoxycyclopentanone (IV) which in turn is providedby reacting the corresponding 4,5 disubstituted-2-cyclopenten-l-one(III) with alkaline hydrogen peroxide. Compounds (III) are prepared bycyclizing the corresponding 2,3-disubstituted levulinaldehyde (II) witha base. The products of the process are biologically active, especiallycompound (I) substituted in the 4-position with 3'-hydroxyocty1 and inthe 5-position with 6'-carboxyhexyl. This compound hasprostaglandin-like activity, especially blood pressure lowering andbronchodilator activity, and is a totally-synthetic dihydroprostaglandinE (dihydro PGE The processes of the invention may also be used to obtaincompounds with prostaglandin-like activity from appropriatelysubstituted naturally occurring cyclopentanones, e.g. those isolatedfrom the Caribbean gorgonian, Plexaura homomalla.

This application is a division of U.S. patent application Ser. No.876,116, filed Nov. 12, 1969, now abandoned, which is acontinuation-in-part of copending application Ser. No. 765,020, filedOct. 4, 1968, now abandoned, which is in turn a continuation-impart ofcopending Ser. No. 702,185, filed Feb. 1, 1968 and now abandoned.

This invention relates to valuable organic compounds, to processes fortheir preparation, and to intermediates useful in said processes. Moreparticularly, it is concerned with4,5-disubstituted-3-hydroxycyclopentanones, which have valuablepharmacological properties; with the corresponding 2,3-epoxides, andother valuable intermediates therefor; and with the processes to preparesaid compounds from known starting materials.

BACKGROUND OF THE INVENTION The compounds contemplated to be provided bythe instant invention are 4,5 disubstituted-3-hydroxycyclopentanones ofFormula I:

ice

wherein R and R are alkyl radicals or alkyl radicals monosubstitutedwith carboxy, carbo (lower)alkoxy, tetrahydropyranyloxy, hydroxy or(lower)acyloxy, the alkyl radicals containing from about 1 to about 20carbon atoms. Compounds of Formula I are pharmacologically active. Inthis connection, special mention is made of the isomer of the compoundof Formula I wherein the hydrogen (H) atoms at the 4- and 5-positionsare in the transstereochemical relationship and wherein R is3'-hydroxyoctyl and R is 6-carboxyhexyl. This compound, also known asdihydroprostaglandin E (dihydro PGE possesses potent blood pressurelowering, bronchodilating and other pharmacodynamic activities. itsureide and thiosemicarbazone derivatives also have bronchodilatingactivity.

The term prostaglandin-like activity is used by those skilled in the artparticularly to describe hypotensive and smooth muscle stimulatingactivity demonstrated by substituted cyclopentane derivatives having thebasic prostaglandin-type structure. This activity was discovered by vonEuler, Arch. Exp. Pathol. PharmakoL, 175, 78 (1934) in lipid-solubleacids extracted in small amounts from the vesicular glands of sheep, andin the seminal fluid of monkeys, sheep and goats. The structure of oneof these acids with prostaglandin-like activity was elucidated by G.Bergstrom and J. Sjovall, Acta Chem. Scand., 14, 1693, 1701, 1706(1960). The compound, 7-[3oz-hydroxy-2-(3- hydroxy-l-octenyl) 5oxocyclopentyl]-heptanoic acid, also called PGE was obtained in purecrystalline form, and then in smaller amounts, only after organizationof a program for the collection of frozen glands of sheep in severalcountries in the northern hemisphere. With this source of PGE, asstarting material, it was then found (S. Bergstrom and J. Sjovall,United Kingdom patent specification No. 1,040,545) that PGB, could behydrogenated using known catalysts for hydrogenating ethenoidunsaturation, for example, platinum catalyst, to the correspondingsaturated acid, dihydro PGE and that this compound possessed valuableprostaglandin-like activity. Other workers sought means to providedihydro 'PGE and similar compounds without the need to isolate PGE fromanimal tissue and secretions. Thus, P. F. Beal, G. S. Fonken and I. E.Pike, in U.S. 3,296,091, describe the bioconversion of arachidonic acidby incubation with sheep vesicular gland tissue into PGE and disclosethat the dihydro PGE can be prepared by hydrogenation, and that it hasprostaglandin-like activity. In a typical example, the homogenate from18.7 kg. of tissue was used, to convert only 35.3 g. of arachidonic acidinto a mixture of four prostaglandins, only one of which was PGE Inaddition to the prostaglandin-like activity reported for dihydro PGE M.Lapidus, N. H. Grant, M. E. Rosenthale, and H. E. Album, in U.S. patentapplication, Ser. No. 672,728, filed Oct. 4, 1967 describe and claim theureido derivative thereof and in U.S. patent application, Ser. No.672,697, filed Oct. 4, 1967, describe and claim the thiosemicarbazonederivative thereof, and disclose that both of these compounds are highlypotent bronchodilating agents. In the present state of the art, asexemplified by the references cited above, prostaglandins are obtainedonly in very small quantities by isolation from tissues by biosyntheses,or by total syntheses, see, for example, George Just and ChaimSimonovitch, Tetrahedron Letters, No. 22, 2093 (1967); and P. F. Bea],HI, I. C. Babcock, F. H. Lincoln, I. Am. Chem. Soc., 88, 3131 (1966);and E. J. Corey et al., ibid., 90, 3245, 3247 (1968). A clear need,therefore, exists for improved means to provide these active and usefulcompounds. The present invention provides such a means, being concernedwith a totally synthetic process to make the 4,5-disubstituted-3-hydroxycyclopentanone ring system present in the basic prostaglandin-typestructure as hereinafter defined.

It is a primary object of the present invention, therefore, to provide4,5-disubstituted-3-hydroxycyclopentanones by total synthesis fromreadily accessible starting materials.

It is another object to provide4,5-disubstituted-3-hydroxycyclopentanones with prostaglandin-likeactivity in high yield from readily accessible starting materialsincluding those of natural origin.

Still another object of this invention is to provide valuableintermediates useful in a totally synthetic process to prepare4,5-disubstituted-3-hydroxycyclopentanones, such as dihydro PGEDESCRIPTION OF THE INVENTION These and other objects readily apparent tothose skilled in the art are easily achieved by practice of the means ofthe instant invention which is, in essence:

First.A process for the preparation of a4,5-disubstituted-3-hydroxycyclopentanone compound of the formula:

-. AMOH wherein R and R are alkyl radicals or alkyl radicalsmono-substituted with carboxy, carbo(lower)alkoxy, tetrahydropyranyloxy,hydroxy, or (lower)acyloxy, the alkyl radicals containing from about 1to about carbon atoms, which comprises reacting a 4,5-disubstituted-2,3-epoxycyclopentanone compound of the formula:

wherein R and R are as defined above, with hydrogen in the presence of acatalyst until hydrogenolysis and formation of said4,5-di-substituted-S-hydroxycyclopentanone is substantially complete.

Special mention is made of a number of valuable embodiments of thisinvention. These are:

Second-A process as first above defined wherein 4- 4 (3'-hydroxyoctyl) 5(6'-carboxyhexyl)-3-hydroxycyclopentanone is prepared by reacting4-(3'-hydroxyoctyl)- 5-(6'-carboxyhexyl)-2,3-epoxycyclopentanone withhydrogen in the presence of a palladized charcoal catalyst;

Third.A process as first above defined wherein 4-(3'-tetrahydropyranyloxyoctyl) 5 (6'-carboxyhexyl)-3-hydroxycyclopentanoneis prepared by reacting 4-(3'-tetrahydropyranyloxyoctyl) 5(6'-carboxyhexyl)-2,3-epoxycyclopentanone with hydrogen in the presenceof a palladized charcoal catalyst.

Fourth.A process as third above defined including the step of reactingsaid 4-(3'-tetrahydropyranyloxyoctyl)-5-(6'carboxyhexyl)-3-hydroxycyclopentanone with an acidic hydrolyzing agentuntil formation of 4-(3'-hydroxyoctyl) S(6'-carboxyhexyl)-3-hydroxycyclopentanone is substantially complete. Thesecond and fourth embodiments provide the valuable compound, dihydro PGEand its stereoisomers.

Fifth.--A process as first above defined wherein 4,5-dimethyl-3-hydroxycyclopentanone is prepared by reacting4,5-dimethyl-2,3-epoxycyclopentanone with hydrogen in the presence of apalladized charcoal catalyst.

Sixth.-A process as first above defined wherein is included the step ofpreparing said 4,5-disubstituted-2,3- epoxycyclopentanone compound by aprocess which comprises contacting a4,5-disubstituted-Z-cyclopenten-l-one of the formula:

wherein R and R are alkyl radicals or alkyl radicals mono-substitutedwith carboxy, carbo(lower)alkoxy, tetrahydropyranyloxy, hydroxy or(lower)acyloxy, the alkyl radicals containing from about 1 to about 20carbon atoms, with alkaline hydrogen peroxide until formation of said4,5-disubstituted-2,3-epoxycyclopentanone is substantially complete.

Seventh.--A process as sixth above defined wherein 4-(3'-hydroxyoctyl) 5(6'-carboxyhexyl)-2,3-epoxycyclopentanone is prepared by contacting4-(3-hydroxyoetyl)-5-(6'-carboxyhexyl)-2-cyclopenten-1-one with alkalinehydrogen peroxide.

Eighth-A process as sixth above defined wherein 4-(3-tetrahydropyranyloxyoctyl)-5-(6 carboxyhexyl)-2,3-epoxycyclopentanone is prepared by contacting4-(3-tetrahydropyranyloxyoctyl) 5 (6'-carboxyhexyl)-2-cyclopenten-l-onewith alkaline hydrogen peroxide.

Ninth.-A process as sixth above defined wherein 4,5-dimethyl-Z,3-epoxycyclopentanone is prepared by contacting4,5-dimethyl-2-cyclopenten-l-one with alkaline hydrogen peroxide.

Tenth.-A process as sixth above defined wherein is included the step ofpreparing said 4,5-disubstituted-2- cyclopenten-l-one compound by aprocess which comprises contacting a 2,3-disubstituted-levulinaldehydeof the formula:

wherein R and R are alkyl radicals or alkyl radicals mono-substitutedwith carboxy, carbo (lower)alkoxy, tetrahydropyranyloxy, hydroxy or(1ower)acyloxy, the alkyl radicals containing from about 1 to about 20car bon atoms, with a base until cyclization to said4,5-disubstituted-Z-cyclopenten-l-one is substantially complete.

Eleventh.A process as tenth above defined including the steps ofseparating, recovering and using as the intermediate in the subsequentsteps, the said 4,5-disubstituted cyclopentene compound wherein thehydrogen atoms at the 4- and S-positions are in the trans-stereochemicalrelationship, substantially free of the cis-isomer.

This embodiment provides, ultimately, pure trans-dihydro PGE which is anaturally-occurring prostaglandin metabolite.

Twelfth-A process as tenth above defined wherein4-(3'-hydroxyoctyl)-5-(6'-carboxyhexyl)-2-cyclopenten-1- one is preparedby contacting2-(3'-tetrahydropyranyloxyoctyl)-3-(6'-carbomethoxyhexyl)levulinaldehydewith a base, followed by acidic hydrolysis of the tetrahydropyranyloxygroup.

Thirteenth-A process as tenth above defined wherein4-(3'-tetrahydropyranyloxyoctyl) 5 (6-carboxyhexyl)- 2-cyclopenten-1-oneis prepared by contacting 2-(3'-tetrahydropyranyloxyoctyl) 3 (6'carbomethoxyhexyl) levulinaldehyde or a2-(3-tetrahydropyranyloxyoctyl)-3- (6'-carboethoxyhexyl)levulinaldehydewith a base.

Fourteenth.A process as tenth above defined wherein4,S-dimethyl-2-cyclopenten-l-one is prepared by contacting2,3-dimethyllevulinaldehyde with a base.

Fifteenth-A process as thirteenth above defined including the steps of(a) Complexing hexanal with a reagent prepared by treating acetylenewith ethylmagnesium bromide and decomposing the Grignard complex formedthereby to produce oct-l-yn-S-ol;

(b) Condensing the product of step (a) with dihydropyran under acidicconditions to produce 2-(oct-1-yn-3- yloxy)tetrahydropyran;

(c) Complexing the product of step (b) with ethylmagnesium bromide,reacting the complex with ethyl orthoformate and decomposing theintermediate found thereby to produce4-(tetrahydropyran-Z-yloxy)-2-nonynal, diethyl acetal;

(d) Reacting the product of step (c) with water under acid conditions toproduce 4-hydroxy-2-nonynal;

(e) Condensing the product of step (d) with dihydropyran under acidconditions to produce 4-(tetrahydropyran-2-yloxy)-2-nonynal;

(f) Hydrogenating the product of step (e) with a noble metal catalyst toproduce 4-(tetrahydropyran-2- yloxy)nonanal;

(g) Complexing the product of step (f) with a reagent prepared bytreating propyne with ethylmagnesium bromide and decomposing theGrignard complex formed thereby to produce 7-(tetrahydropyran-Z-yloxy) 2dodecyn-4-ol;

(h) Reacting t-butylacetoacetate with sodium hydride and condensing theanion formed thereby with ethyl 7-bromoheptanoate to produce2-acetylnonadioic acid, l-t-butyl ester, 9-ethyl ester;

(i) Esterifying the product of step (g) with methanesulfonyl chlorideunder basic conditions to produce 7- (tetrahydropyran-Z-yloxy) 2dodecyn-4-ol, methanesulfonate;

(j) Reacting the product of step (h) with sodium hydride and condensingthe anion formed thereby with the product of step (i) to produce2-acetyl-2-[1-(1-propynyl)- 4 (tetrahydropyran 2 yloxy)nonyl]nonanedioic acid, l-t-butyl ester, 9-ethyl ester;

(k) Hydrolyzing the product of step (j) under acidic conditions toproduce 2 'acetyl-2-[4-hydroxy-l-(1-propynyl)-nonyl]nonanedioic acid,1-t-'butyl ester, 9-ethyl ester;

(l) Acetylating the product of step (k) with acetic anhydride andpyridine to produce 2-acetyl-2- [4-hydroxy-1-(l-propynyl)nonyl]nonanedioic acid, l-t-butyl ester, 9-ethyl ester,acetate;

(in) Monohydrogenating the product of step (1) with hydrogen and apalladium on calcium carbonate catalyst to produce 2-acetyl-2-[4-hydroxy-1-(1-propenyl)nonyl] nonanedioic acid, l-t-butyl ester,9-ethyl ester, acetate;

(:1) Decarboxylating the product of step (In) with p-toluenesulfonicacid or with calcium iodide to produce 8-acetyl-12-hydroxy-9-(lpropenyl)-heptadecanoic acid, ethyl ester, acetate;

(0) Saponifying the product of step (11) with aqueous ethanolic sodiumhydroxide to produce 8-a-cetyl-12-hydroxy-9-( l-propenyl)heptadecanoicacid;

(p) Esterifying the product of step (0) with ethereal diazomethaneto-produce 8-acetyl-12-hydroxy-9-(l-propenyl)heptadecanoic acid, methylester;

(q) Condensing the product of step (p) with dihydropyran under acidicconditions to produce 8-acetyl-l2- (tetrahydropyranyl-Z-oxy)-9-(lpropenyl)heptadecanoic acid, methyl ester; or

(s) Decarboxylating the product of step (j) with calcium iodide toproduce 8-acetyl-12-hydroXy-9-(l-propynyl)-heptadecanoic acid, ethylester; and

(t) Monohydrogenating the product of step (s) with hydrogen and apalladized charcoal catalyst to produce 8-acetyl-12-hydroXy-9-(lpropenyl)heptadecanoic acid, ethyl ester; and

(u) Condensing the product of step (t) with dihydropyran under acidicconditions to produce 8-acetyl-9-(1- propenyl)-l2- (tetrahydropyran 2yloxy)heptadecanoic acid, ethyl ester; or

(v) Condensing the product of step (s) with dihydropyran under acidicconditions to produce 8-acetyl-9- (1-propynyl)-l2-(tetrahydropyran 2yloxy)heptadecanoic acid, ethyl ester; and

(w) Monohydrogenating the product of step (v) with hydrogen and apalladized charcoal catalyst to produce 8-acetyl-9-(1-propenyl) 12(tetrahydropyran-Z-yloxy) heptadecanoic acid, ethyl ester; and

(r) Ozonizing the product of step (q), (u) or (w), then decomposing theozonide produced thereby with zinc dust in acetic acid to produce2-(3'-tetrahydropyranyloxyoctyl)-3-(6-carbomethoxyhexyl)levulinaldehydeor 2-(3'- tetrahydropyranyloxyoctyl) 3 (6'-carboethoxyhexyl)levulinaldehyde.

Sixteenth.--A process for the preparation of a4,5-disubstituted-3-hydroxycyclopentanone compound of the formula:

H0 0 OH (dihydroprostaglandln E including the steps of aa) Esterifying4-(3'-hydroxy 1' octenyl)-5-(6'-carboxy-2'-hexenyl)-2-cyclopenten-l-oneisolated from the Caribbean gorgonia Plexaura homomalla withmethanesulfonyl chloride under basic conditions to produce 4-(3'-methanesulfonyloxy-1-octenyl) 5(6-carboxy-2'-hexenyl)-2-cyclopenten-1-one;

(bb) Inverting the configuration of the oXy-substituent at the3-position in the compound of step (aa) by refluxing in acetone withtetraethylammonium formate to produce 4-(3-formyloxy-1'-octenyl) 5(6'-carboxy- 2'-hexenyl -2-cyclopenten-1-one;

(cc) Forming the epoxide of the compound of step (bb) and saponifyingthe product by reacting with alkaline hydrogen peroxide to produce4-(3-hydroxy-1'- octenyl)-5-(6' carboxy 2hexeny1)-2,3-epoxycyclopentanone;

(dd) Hydrogenating the compound of step (cc) with hydrogen in thepresence of a palladized charcoal catalyst to produce4-(3'-hydroxyoctyl)-5-(6'-carboxyhexyl)-3- hydroxycyclopentanone.

Also contemplated by the instant invention are compounds of the formulawherein R and R are alkyl radicals or alkyl radicals monosubstitutedwith carboxy, carbo (lower)alkoxy, tetrahydropyranoxy, hydroxy orlower(acyloxy), the alkyl radicals containing from about 1 to about 20carbon atoms. These compounds are valuable intermediates in the processof this invention. Special mention is made of several importantcompounds within the above formula. These are:

4-(3'-hydroxyoctyl) 5 (6'-carboxyhexyl)-2,3-epoxycyclopentanone (R is6'-carboxyhexyl; R is 3'-hydroxyoctyl).

4-(3' acetoxyoctyl) 5 (6-carboethoxyhexyl)-2,3- epoxycyclopentanone (Ris 6-carboethoxyhexyl; R is 3 '-acetoxyoctyl)4-(3'-tetrahydropyranyloxyoctyl) 5 (6' carbomethoxyhexyl) 2,3epoxycyclopentanone (R is 6'-carbomethoxyhexyl; R is3'-tetrahydropyranyloxyoctyl).

4-(3' tetrahydropyranyloxyoctyl) 5 (6carboxyhexyl)-2,3-epoxycyclopentanone (R is 6-carboxyhexyl; R is3'-tetrahydropyranyloxyoctyl).

In addition there are contemplated:

4-(3' tetrahydropyranyloxyoctyl) 5(6'-carbomethoxyhexyl)-2-cyclopenten-1-one.

4-(3 tetrahydropyranyloxyoctyl) 5 (6'-carboxyhexyl)-2-cyclopenten-l-one.These form a family of compounds of the formula H R1 m n i if 3 whereinR is 6-carbomethoxyhexyl and R is 3'-tetrahydropyranyloxyoctyl; and

R is 6-carboxyhexyl and R is 3'-tetrahydropyranyloxyoctyl, respectively,

I 8 In addition there is contemplated a sub-genus of com pounds ofFormula I which are those of Formula Ia:

n ozo I wherein R is hydrogen or (lower) alkyl (of up to about 6 carbonatoms) and R is tetrahydropyranyl or acyl of from about 1 to about 20carbon atoms.

Valuable species of Formula Ia are 4- (3 '-acetoxyoctyl) -5-6'-carboethoxyhexyl -3-hydroxycyclopentanone, wherein R is ethyl and Ris acetyl; and

4-(3'-tetrahydropyranyloxyoctyl)-5-(6-carboxyhexy1)-3-hydroxycyclopentanone, wherein R is hydrogen and R is tetrahydropyranyl.

Furthermore, there are contemplated as valuable intermediates thefollowing substituted levulinaldehydes:

2- 3 -hydroxyoctyl) -3- 6-carboxyhexyl) levulinaldehyde.

2- 3 -tetrahydropyranyloxyoctyl -3- 6'-carboxyhexyl) levulinaldehyde.

2- (3 '-tetrahydropyranyloxyoctyl -3- 6-carbomethoxyhexyllevulinaldehyde.

2- (3 -tetrahydropyrany1oxyoctyl) -3- 6'-carboeth0xyhexyl)levulinaldehyde.

2- (3 -acetoxyoctyl) -3- 6'-carboethoxyhexyl) levulinaldehyde.

R is 6'-carboxyhexyl and R is 3-hydroxyoctyl;

R is 6-carboxyhexyl and R is 3-tetrahydropyranyloxyoctyl;

R is 6'-carbomethoxyhexyl and R is 3'-tetrahydropyranyloxyoctyl;

R is 6'-carboethoxyhexyl and R is 3'-tetrahydropyranyloxyoctyl; and

R is 6-carboethoxyhexyl and R is 3-acetoxy0ctyl,

respectively.

In addition, there are contemplated as valuable intermediates thefollowing:

8 acetyl 12 (tetrahydropyran-Z-yloxy)-9-(l-propenyl)heptadecanoic acid,methyl ester.

8-acetyl 12 hydroxy-9-(1-propeny1)heptadecanoic acid, methyl ester.

8-acetyl 12 hydroXy-9-(1-propenyl)heptadecanoic acid.

8-acetyl 12 hydroXy-9-(1-propenyl)heptadecanoic acid, ethyl ester,acetate.

8-acetyl 12 hydroXy-9-(l-propynyl)-heptadecanoic acid ethyl ester.

8-acetyl 12 hydroxy-9-(1-propenyl)heptadecanoic acid, ethyl ester.

8 acetyl 9 (l-propynyl)-l2-(tetrahydropyran-2- yloxy)heptadecanoic acid,ethyl ester.

8 acetyl 9 (l-propenyl)-12-(tetrahydropyran-2- yloxy)heptadecanoic acid,ethyl ester.

2-acetyl-1-[4 hydrXy-1-(1-jropenyl)nonyl]nonanedioic acid, l-t-butylester, 9-ethyl ester, acetate.

2 acetyl-2-[4-hydroxy-1-(1 propynyl)nonyl]nonanedioic acid, l-t-butylester, 9-ethyl ester, acetate.

2-acetyl 2 [4-hydroXy-1-(l-propynyl)nonyl]nonanedioic acid, l-t-butylester, 9-ethyl ester.

Z-acetyl 2 [1 (1-propynyl)-4-(tetrahydropyran-Z- yloxy)nonyl]nonanedioicacid, l-t-butyl ester, 9-ethyl ester. These acetyl acids and esterscomprise a family of the formula wherein R is methyl, R is hydrogen; Ris tetrahydropyranyloxy and W is a carbon-to-carbon double bond;

R is methyl, R is hydrogen, R is hydroxy and W is a carbon-to-carbondouble bond;

R and R are hydrogen, R is hydroXy and W is a carbonto-carbon doublebond;

R is ethyl, R is hydrogen, R is acetoxy and W is a carbon-to-carbondouble bond;

R is ethyl, R is hydrogen, R is hydroxy and W is a carbon-to-carbontriple bond;

R is ethyl, R is hydrogen, R is hydroxy and W is a carbon-to-carbondouble bond;

R is ethyl, R is hydrogen, R is tetrahydropyranyloxy and W is acarbon-to-carbon triple bond;

R is ethyl, R is hydrogen, R is tetrahydropyranyloxy and W is acarbon-to-carbon double bond;

' R is ethyl, R is carbo-t-butoxy, R is acetoxy and W is acarbon-to-carbon double bond;

R is ethyl, R is carbo-t-butoxy, R is acetoxy and W is acarbon-to-carbon triple bond;

R is ethyl, R is carbo-t-butoxy, R is hydroxy and W is acarbon-to-carbon triple bond; or

R is ethyl, R is carbo-t-butoxy, R is tetrahydropyranyloxy and W is acarbon-to-carbon triple bond.

Also contemplated as an intermediate is:

2-acety1nonadioic acid, l-t-butyl ester, 9-ethyl ester.

Also contemplated as intermediates are:

7-(tetrahydropyran-2-yloxy)-2-dodecyn-4-ol,

methanesulfonate. 7- tetrahydr opyran-Z-yloxy -2-dodecyn-4-ol.

These form a family of the formula OTHP wherein THP is tetrahydropyranyland wherein R is methanesulfonyl or hydrogen.

In addition as valuable intermediates there are contemplated:

4-(tetrahydropyran-Z-yloxy)nonanal.

4- (tetrahydropyran-Z-yloxy -2-nonynal. 4-hydroXy-2-nonynal.4-(tetrahydropyran-Z-yloxy)-2-nonynal, diethyl acetal.

These nonanal derivatives comprise a family of the formula wherein R istetrahydropyranyloxy, R is CH0 and Y is carbon-to-carbon single bond; Ris tetrahydropyranyloxy, R is CH0 and Y is a carbon-to-carbon triplebond; R is hydroxy, R is CH0 and Y is a carbon-to-carbon triple bond; orR is tetrahydropyranyloxy, R is CH(OCH CH z and Y is a carbon-to-carbontriple bond.

Also as valuable intermediates there are contemplated:

4-(3'-methanesulfonyloxy-1'-octenyl) 5 (6-carboxy-2'-hexenyl)-2-cyclopenten-1-one.

4-(3-formyloxy 1 octenyl) 5 (6' carboxy 2- hexenyl)-2-cyclopenten-1-one.

4-(3'-hydroxy 1' octenyl) 5 (6' carboxy 2'-hexenyl)-2,3-epoxycyclopentanone.

When used herein and in the appended claims, the term alkyl contemplateshydrocarbon radicals, straight and branched chain, containing from about1 to about 20 carbon atoms, and includes methyl, ethyl, n-propyl,ipropyl, n-butyl, t-butyl, n-penty], 3-methylpentyl, n-hexyl, n-heptyl,n-octyl, n-nonyl, n-decyl, n-undecyl, n-dodecyl, n-tridecyl,n-tetradecyl, n-pentadecyl, n-hexadecyl, nheptadecyl, n-octadecyl,n-nondecyl, n-eicosyl and the like. The term carbo(lower)alkoxy refersto carboxyl groups of the formula CO R wherein R is (lower) alkyl offrom about 1 to about 6 carbon atoms, as illustrated above including upto n-hexyl. The term (l0wer) acyloxy contemplates an organic radicalderived from an organic acid containing up to about 7 carbon atoms byremoval of the hydroxyl group and is illustrated by formyloxy, acetoxy,propionyloxy, n-butyroyloxy, secbutyroyloxy, n-pentanoyloxy,n-hexanoyloxy, cyclopentanoyloxy, benzoyloxy, and the like.

1 1 The process of the present invention in its first foureen abovementioned embodiments may be represented as follows:

E R H R R H alkaline base 0 H1O:

H R R H H R R H H hydrogen, r

catalyst 0 O OH O IV I wherein R and R are as hereinabove defined.

The first step (1) involves the conversion of the levulinaldehyde (II)with base, e.g., an alkali metal or alkaline earth metal hydroxide,carbonate or obvious chemical equivalent thereof, preferably sodiumhydroxide, under cyclizing conditions, into the 2-cyclopenten-l-one(HI). In one manner of proceeding a solution or suspension of thealdehyde (II) in about 200 parts by weight of water is treated withabout of its total volume of N sodium hydroxide solution at atemperature of from about 0 C. to about 50 C., preferably from about 20C. to about 30 C. until cyclization to the corresponding2-cyclopentan-l-one is substantially complete. The time required willvary from about 5 minutes to about 2 to 3 hours, but in most cases, atabout 25 C., minutes is suflicient. The intermediate of Formula III canbe recovered by any conventional means. One convenient procedure is toextract the reaction mixture with a water-immiscible organic solvent,such as ether, ethyl acetate, methylene chloride, and the like, then towash and dry and finally to distill the solvent off of the intermediate.The intermediate of Formula III can be purified, if desired, bydistillation in a vacuum or by recrystallization.

Nuclear magnetic resonance studies indicate the product of step 1) toconsist mainly of the 4,5-trans-disubstituted ketone (IIIa) H-- H o:

The 4,5-cis-disubstituted ketone is depicted by Formula IIIb:

lIIb

In the case where R =R =methyl, the NMR spectrum of IIIa exhibits amultiplet for the C-5 proton with coupling constants of 7.5 and 2.5cps., which arise from the coupling with the 0-5 methyl protons and theC-4 proton, respectively. The 2.5 cps. coupling constant of the C-4 andC-5 protons is indicative of a dihedral angle of 120 which is consistentwith the trans configuration for these protons. Accordingly, it may beassumed that the products of the instant process possess mainly the4,5-trans-configuration corresponding to the configuration of thenatural prostaglandin series. In one embodiment of this invention, thetrans isomer (IIIa) is separated from the cis isomer (IIIb) to provide(after using IIIa in steps (2) and (3)) a product containing the totallysynthetic prostaglandin of the natural configuration. The separation ofisomers is accomplished by any conventional means used in this series,for example, chromatography, gas liquid chromatography, countercurrentdistribution and obviously equivalent means can be used.

The second step (2) involves the treatment of the 4,5 disubstituted 2cyclopenten-l-one of Formula III with alkalin hydrogen peroxide to formthe corresponding 4,5 disubstituted 2,3 epoxycyclopentanone of FormulaIV. The conditions for this conversion involve carrying out the reactionin an alkaline medium (aqueous alkali metal or alkaline earth metalhydroxides, carbonates, or obvious chemical equivalents thereof)preferably an aqueous sodium hydroxide medium with hydrogen peroxide ofmoderate concentrations, e.g., 15 to 50%, preferably about 30%, beingmixed with the 2- cyclopenten-l-one before adding the alkali. Thereaction preferably is conducted at low temperatures, between about thefreezing point of the mixture and about 35 C. In one manner ofproceeding, a solution of 10% sodium hydroxide is added to an ice coldmixture comprising the cyclopenten-l-one of Formula III and about 3parts by weight of 30% hydrogen peroxide, based on the weight of thecyclopenten-l-one. The reaction is substantially complete after about 20minutes at 0 C. The intermediate 4,5 disubstituted 2,3epoxycyclopentanone of Formula IV is recovered by any conventionalmeans. One convenient technique comprises adding about 3 volumes ofwater to the reaction mixture, extracting the diluted mixture with awater-immiscible organic solvent, such as ether, ethyl acetate,methylene chloride and the like, washing and drying the extract andremoving the solvent by distillation, leaving the compound of Formula IVas a residue.

The third step (3) involves hydrogenolysis of the 4,5-disubstituted-2,3-epoxycyclopentanone by reaction with hydrogen over acatalyst, such as a noble metal catalyst, finely divided or supported,on a carrier, for example, platinum or palladium, or palladium on carbonor palladium on charcoal (which is preferred) until formation of the 4,5disubstituted 3 hydroxycyclopentanone is substantially complete. In onemanner of proceeding, the 4,5 dialkyl 2,3 epoxycyclopentanone in about 4volumes of a solvent, such as methanol, is mixed with palladizedcharcoal, then reacted with hydrogen at a temperature from about 5 C. toabout 50 C., preferably at about 25 C. at low to moderate pressures,e.g., from about 1 to about 3 atmospheres, preferably about 1 atmosphereuntil absorption of the equivalent amount or a slight excess, e.g., upto about 1.1 moles of hydrogen is substantially complete. The instantproducts of Formula I are recovered by any conventional technique. Oneconvenient means comprises filtering the reaction mixture and distillingoff the solvent to leave the product as a residue. It may be purified bydistillation in a vacuum or by crystallization from an appropriatesolvent such as a lower alkanol, e.g., methanol or a lower ketone, or alower ester, such as ethyl acetate.

Even where the products of Formula I are prepared without separation ofthe precursor products of Formula III into their trans and cis-isomers111a and IIIb, respectively, the aforesaid products still consist mainlyof the isomer in which the hydrogens at the 4 and 5-positions are in thetransconfiguration. This is shown for the case in which R =R =methyl bythe transformation of the mixture of 4,5 dimethyl 3hydroxycyclopentanones by base to a mixture containing thecyclopentenones 111a and IIIb in a ratio of 7:1. This mixture wasseparated by preparative gas liquid chromatography into its twocomponents and proton NMR spectroscopy was used to confirm thestructures assigned to them. For example, the spectrum of Compound IIIbin which R =R =methyl displayed a quintet for the C-5 proton with a 7.2cps. coupling constant. This pattern arises from overlapping quartetsresulting from coupling with the C-5 methyl protons and the C-4 proton.The 7.2 cps. coupling constant for the C-4 and C-5 protons is indicativeof a dihedral angle of 0 which reveals the cis-configurationalrelationship for these protons.

The process of this invention represented by the fifteenthabove-mentioned embodiment may be represented in the following pathway:

7 wherein THP is tetrahydropyranyl p-TS is p-toluenesulfonic acid, Ac isacetic anhydride and HAO is acetic acid. The reagents are illustrative,but are not limiting. As will be obvious to those skilled in the art,equivalents will be available to accomplish the stated conversion step.

As is mentioned hereinabove, compounds 1121, VII- XIH and XVI-XXIV arewithin the purview of this invention.

The procedures for carrying out the fifteenth embodiment are exemplifiedin detail hereinafter. Generally, treatment of hexanal (V) withethynylmagnesium halide to obtain the alcohol (VI) and the preparationof its THP ether (VII) is accomplished essentially as reported in J.Med. Chem. 8, 41 (1965). Subjecting the Grignard derivative of VII toethyl orthoformate and decomposing with ammonium chloride affords theacetal (VIII). Acid hydrolysis of the acetal provides thehydroxyaldehyde (IX) which will decompose on distillation. However, therather impure IX can be converted to its THP ether (X), which distillswith much less decomposition. Hydrogenation of X, e.g., with Pd/C inethyl acetate, yields a stable aldehyde (XI). Treating (XI) withpropynyl magnesium halide and decomposing the complex, e.g., withammonium chloride, provides a distillable, viscous alcohol (XII), whichcan be transformed into the mesylate ()QHI) with mesyl chloride inpyridine. The mesylate is very unstable and preferably is usedimmediately in step (i). The ethyl 7-bromoheptanoate (XIV) alkylation oft-butylacetoacetate (XV) provides a nonadioic diester (XVI) which isalkylated with the mesylate (XIII), e.g., in the presence of an alkalimetal hydride, e.g., sodium hydride. Acid hydrolysis of the THP ether(XVII) followed, e.g., by chromatography, affords the alcohol '(XVIH).Acetylation of (XVIII), e.g., with acetic anhydride preferably in thepresence of pyridine provides the acetate (XIX), which ismonohydrogenated, e.g., with a 2% palladium/CaCO catalyst in ethylacetate, to produce the propene derivative (XX). Decarboxylation of XXto the di-ester (XXI) can be achieved with either p-TSA/IOO" C./0.5 hr.or with CaI 150 C./1.5 hr. Hydrolysis of XXI with 0.5 N sodium hydroxidein 50% aqueous ethanol provides XXII which is esterified withdiazomethane in ether to produce XXIII. Treatment of XXIII in benzenewith dihydropyran and p-TSA affords XXIV. Alternatively, decarboxylationof XVII is achieved with Ca-I 150 C./25 min., to produce the alcohol(XVII-a). Monohydrogenation of XVII-a, e.g., with 10% Pd/C in ethylacetate to produce the propane derivative (XVII-b). Treatment of XVII-bwith dihydropyran and p-TSA in benzene affords XXIV. The final twoalternative steps may be reversed by treating XVII-a in benzene withdihydropyran and p-TSA to produce XVI I-c followed by monohydrogenationof XVII-c, e.g., with 10% Pd/C in ethyl acetate to produce the propenederivative (XVII-d). Ozonolysis of XVII-d, followed by Zn/HAc work-upgives the desired aldehyde IIa which is converted by the embodimentsdescribed above to dihydroprostaglandin E The process of this inventionrepresented by the sixteenth above-mentioned embodiment may berepresented by the following pathway:

(aa) l CH S0 Cl/pyrldine (cc) lalkaline H 0 (XXVIII) \o swi Pd/C 0.. on(XXIX) (dihydroprostaglandin E1) Use of the processes of the inventionwill also lead to compounds having prostaglandin-like activity whenapplied to substances derived from naturally occurring cyclopentanonessuch as 4 (3-hydroxy-1'-octenyl)-5-(6- carboxy-2'-hexenyl)-2-cyclopentenl one (XXV) which has recently been isolated (along with its acetate)from the Caribbean gorgonia Plexaura homomalla (A. J. Weinheimer and R.L. Spraggins, Paper 41, Division of Medicinal Chemistry, Abstracts ofPapers, 158th National Meeting of American Chemical Society, Sept. 7-12,1969, Craftsman Press, Inc., Bladensburg, Md.).

Thus XXV, isolated directly from natural sources or throughsaponification of the naturally occurring acetate, is converted withmethanesulfonyl chloride in pyridine to its mesylate XXVI, which isrefluxed in acetone with tetraethylammonium formate, a procedurepreviously used to invert the configuration of hydroxyl groups [8. G.Levine, N. H. Eudy and C. F. Lefiier, J. Org. Chem., 31, 3995 (1966); L.F. Fieser and M. Fieser, Reagents for Organic Synthesis, John Wiley andSons, Inc., New York, 1967, p. 1136] The formate product XXVII treatedwith alkaline hydrogen peroxide gives the epoxide XVIII (epoxidationbeing accompanied by saponification), and the latter, on hydrogenationover a palladium catalyst is converted to an alcohol product XXIXcontaining dihydroprostaglandin E As has been mentioned hereinabove, thecompounds prepared by the instant process have valuable pharmacodynamicproperties. Notably, a large group of naturally occurring, biologicallyactive prostaglandins and prostaglandin metabolites fall within thescope of Formula I. Thus, dihydro PGE which possesses potent bloodpressure lowering and bronchodilator properties is a compound of Formula[I wherein R is 3'-hydroxyoctyl and R is 6'-carboxyhexyl, in a transrelationship. This makes them useful in the control of hypertension andbronchoconstriction in valuable domestic animals and in laboratoryanimals such as mice, rats and rabbits. Furthermore, as also is metionedabove, the ureide of dihydro PGE; and the thiosemicarbazone of dihydroPGE, are surprisingly eifective as bronchodilators, which makes themuseful to treat experimentally-induced respiratory disorders in warmblooded lower animals, such as guinea pigs.

By way of illustration, for the purposes mentioned above, thebis-p-dimethylaminophenyl ureide of dihydro PGE (also known as1,3-bis(p-dimethylaminophenyl)-1- [[7-[3-hydroxy-2-(3-hydroxyoctyl)oxocyclopentyl1- 5-heptanoyl]]urea) can be administered in a variety ofdosage forms, the oral route being used primarily for maintenancetherapy while injectables tend to be useful in acute emergencysituations. Inhalation (aerosols and solution for nebulizers) seems tobe somewhat faster acting than other oral forms but slower thaninjectables and this method combines the advantages of maintenance andmoderately acute stage therapy in one dosage unit.

As is disclosed in Ser. No. 672,728 filed Oct. 4, 1967, now US. PatentNo. 3,501,525, the daily dose requirements vary with the particularcomposition being employed and the severity of the symptoms beingpresented. The dosage varies with the size of the patient. With largeanimals, e.g., about 70 kilograms average body weight, by the oralinhalation route, with, for example, a hand nebulizer or a pressurizedaerosol dispenser, the ordinarily effective dose from about 50milligrams to about 150 milligrams of the instant compounds every fourhours, as needed. By the oral ingestion route, preferably sublingually,the effective dose is from about 250 to about 1000 mg., preferably fromabout 500 to about 750 mg., up to a total of about 3000 mg. per day. Bythe intravenous route, the ordinarily effective dose is from about 50milligrams to about 250 milligrams, preferably about 175 milligrams perday.

For dosage units, the said prostaglandin ureide compound can becompounded into any of the usual oral dosage forms including tablets,capsules and liquid preparations such as elixirs and suspensionscontaining various coloring, flavoring, stabilizing and flavor maskingsubstances. For compounding oral dosage forms the active ingredient canbe diluted with various tableting materials such as starches of varioustypes, calcium carbonate, lactose, sucrose and dicalcium phosphate tosimplify the tableting and capsulating process. A minor proportion ofmagnesium stearate is useful as a lubricant.

For administration by the oral inhalation route with conventionalnebulizers or by oxygen aerosolization it is convenient to provide thesaid prostaglandin ureide compound in dilute aqueous solution orsuspension preferably at concentrations of about 1 part of medicament tofrom about 100 to 200 parts by weight of total preparation. Entirelyconventional additives may be employed to stabilize these preparationsor to provide isotonic media, for example, sodium chloride, sodiumcitrate, citric acid, sodium bisilfite, and the like may be used.

For administration as a self-propelled dosage unit for administering themedicament in aerosol form suitable for inhalation therapy, thecompounds can be used in compositions comprising the medicamentsuspended in an inert propellant (such as a mixture ofdichlorodifluoromethane and dichlorotetrafluoroethane) together with aco-solvent, such as ethanol, flavoring materials and stabilizers.Instead of a co-solvent there can also be used a dispensing agent suchas oleyl alcohol. Suitable means to employ the aerosol inhalationtherapy technique are described fully in US. 2,868,691 and 3,095,355.

The following procedures illustrate useful means to obtain startingmaterials employed in the instant process.

PROCEDURE A 2,3-dimethyllevulinaldehyde (a) 2 methyl-Z-(I-methyl 2butenyl)acetoacetic acid, ethyl ester.-Add a mixture of 100 g. of2-penten- 4-ol and 25 ml. of pyridine dropwise over /2 hour to 115 g. ofphosphorus tribromide cooled in an ice bath. After stirring for 1 hourat room temperature, the mixture is distilled to obtain 135 g. of4-bromo-2-pentene, B.P. 22-38/ 12 mm.

Add ethyl ot-methylacetoacetate ml.) dropwise to an ice-cooled mixtureof 40 g. of 50% sodium hydride-oil dispersion in 500 ml. benzene and 300ml. dimethylformamide with stirring under nitrogen. Stir at roomtemperature for 15 min., add g. of the above 4-bromo-2-pentene dropwiseand reflux the resulting suspension for 1 hour. Add the cooled mixtureto water and extract with ether. Evaporate the washed and dried extractand distill the residue to obtain 121 g. of the product, B.P. 97100/ 3mm.,

Found (percent): C, 67.58; H, 9.26. Calcd. for C H O (percent): C,67.89; H, 9.50.

(b) 3,4-dimethyl-5-hepten-2-one.-Stir and reflux a mixture of 62.6 g. of2-methyl-2-(l-methyl-Z-butenyl) acetoacetic acid, ethyl ester and 200 g.of barium hydroxide in 1.5 liters of water for 2 days. Acidify thecooled mixture with concentrated hydrochloric acid and extract withether. Distill the washed and dried extract to obtain 35.3 g. of theproduct, B.P. 7377/20 mm.,

Found (percent): C, 77.38; H, 11.55. Calcd. for C H O (percent): C,77.09; H, 11.50.

(c) 2,3-dimethyllevulinaldehyde.-Cool a mixture of 10 g. of3,4-dimethyl-5-hepten-2-one, 5.5 ml. of pyridine and 200 m1. methylenechloride in a dry ice-acetone bath and ozonize (O 8 p.s.i., 110 volts,flow rate .04) for 70 min. Add the cold solution to 6.0 g. of zinc dust,stir and treat with 13 ml. of acetic acid. Stir the mixture at roomtemperature by cooling with an ice bath when necessary, for 2 hours.Treat the mixture with aqueous Na CO until basic, adjust to pH 5 withhydrochloric acid, separate and extract with additional methylenechloride. Evaporate and washed and dried extract and distill the liquidto obtain 5.7 g. of 2,3-dimethyllevulinaldehyde B.P. 6062/ 2.5 mm.,

Reported B.P. 7679/ 12.5 mm. in Helv. Chim. Acta 42, 2746 (1959).

DESCRIPTION OF THE PREFERRED EMBODIMENTS The following examplesillustrate the use of the processes of this invention to prepare anumber of valuable compounds. The examples are merely illustrative andare not to be construed to limit the scope of the invention in anymanner whatsoever.

EXAMPLE 1 2- (3 -hydroxyoctyl) -3- 6'-carboxyhexyl) -levulinaldehyde andtetrahydropyranyl ether thereof The process of Procedure A is repeatedsubstituting stoichiometrically-equivalent amounts of ethyla-(6-carboethoxyhexyl)acetoacetate and6,14-di-tetrahydropyranyloxy-ll-methanesulfony1oxy-9-nonadecene asstarting materials in step (a). The product of step (c) is suspended inaqueous methanol containing about 5% by weight of hydrogen chloride andwarmed to 50 C. for 1 hour. Evaporation of the solvent leaves the titleproduct as a residue.

EXAMPLE 2 2-(3'-tetrahydropyranyloxyoctyl) 3(6'-carbomethoxyhexyl)levulinaldehyde and2-(3-tetrahydropyranyloxyoctyl)-3-(6'-carboethoxyhexyl)levulinaldehyde(a) Oct-1-yn-33-ol.Acetylene is passed through 2 solid cO -acetone trapsand bubbled through 1 liter of tetrahydrofuran (THF) for 10 minutes.With acetylene bubbling through the solution, 335 ml. of 3 M EtMgBr- EtO is added with stirring in small portions over 1 hour. The reactionmixture foams and refluxes slowly during addition of the Grignardreagent. The resulting brown suspension is saturated with acetylene foranother 10 minutes, cooled to 5 C., acetylene is discontinued and themixture is cooled to 5 C. with a MeOH-ice bath. Freshly distilledhexanal (100 g.) is added dropwise to the stir-red mixture over 1.25 hr.while keeping the temperature at C. The suspension is stirred at 0 C.for 1 hour, stirred at room temperature for 16 hours, added to 3 litersof saturated NH Cl and extracted with ether. After washing with water,the ether solution is dried, evaporated and the residue distilled togive 47 g. of oct-lyn-3-ol, B.P. 85-90 C./ 1.5 mm. (reported B.P. 75-85C./10 mm., J. Med. Chem. 8, 41 [1965]),

A2}. 3.1;: (8.) (hydroxyl and ethynyl C-H) NMR: 4.39 (multiplet, C-3 H),3.41 (s., hydroxy H), 2.47 (d., J =2 c.p.s., C-l H) p.p.m.

(b) 2-(oct-1-yn-3-yloxy)tetrahydropyran.-A mixture of 195 g. ofoct-1-yn-3-ol and 153 g. of dihydropyran (purified by standing over KOHpellets for 2 days and distilling from CaH is stirred and cooled to 10C., treated with 6 drops of cone. HCl, stirred at 10 C. for /2 hr. andkept at room temperature for 3 days (only 1 day necessary). The mixtureis treated with 3 pellets of KOH and distilled to obtain 279.4 g. of2-(oct-1-yn-3- yloxy)tetrahydropyran, B.P. 70-88 C./0.3 mm. [reportedB.P. 74 'C./0.5 mm., J. Med. Chem. 8, 41 (1965 )1,

A21; 3.1 (w.) (ethynyl C-H).

NMR: 2.42 (quartet, ethynyl H) p.p.m.

(c) 4- (tetrahydropyran-Z-yloxy) 2 nonynal, diethyl acetal.-A solutionof 192.2 g. of 2-(oct-1-yn-3-yloxy) tetrahydropyran in 250 ml. of etheris added dropwise under nitrogen during hour to 410 ml. of 3 MEtMgBrether with stirring. After refluxing for /2 hour, 177 g. of ethylorthoformate is added and the mixture refluxed for 18 hours. Theresulting suspension is added to 2 liters of saturated NH Cl andextracted with ether. After washing with water, the ether extract isdried, evaporated and the residue distilled to obtain 219.8 g. ofproduct, B.P. 140- 160 C./0.2 mm. An analytical sample exhibits B.P. 143C./ 0.15 mm.,

NMR: 5.32 (s., 01 H), 1.25 (t., J=7 c.p.s., ethyl CH Analysis-Found(percent): C, 69.19; H, 10.11.

c H o, requires (percent): C, 69.19; H, 10.32.

(d) 4-hydroxy-2-nonynal.-A solution of 216.8 g. of 4-(tetrahydropyran-Z-yloxy)-2nonyna1, diethyl acetal in 1.1 liters of THFis treated with 210 ml. of 30% H 80 and the mixture stirred at 25 C. for5.5 hr. The mixture is diluted with 4 liters of water and extracted withether. After washing with KHCO and water, the ether extract is dried andevaporated to yield 169.1 g. of 4-hydroxy-2-nonyna1, hilt; 3.0 (M)(hydroxyl), 4.5 (w.) (O=C), 5.93 (s.) (aldehyde carbonyl) (e)4-(tetrahydropyran-Z-yloxy)-2-nonynal. A stirred mixture of 169 g. of4-hydroxy-2-nonynal and 127 g. of dihydropyran is treated with 12 dropsof concentrated HCl and the reaction temperature maintained for /2 hourat 20-25 C. with an ice bath. After stirring at room temperature for 4hours, the mixture is diluted with 1 liter of ether, washed with 5% KHCOwater and dried. Evaporation and distillation of the residue affords114.5 g. of 4-(tetrahydropyran 2 yloxy)-2-nonynal B.P. 100- 120 C./ 0.2mm.,

122., 4.53 (M) (C C), 5.95 (s.) (aldehyde carbonyl) p.

(f) 4 (tetrahydropyran-2-yloxy)nonanal.A solution of 22.9 g. of4-(tetrahydropyran-Z-yloxy)-2-nonynal in 75 ml. of ethyl acetate isadded to 4.5 g. of Pd/C prehydrogenated in 100 ml. of ethyl acetate andthe mixture is hydrogenated at 25 C. and atmospheric pressure. When 2.1equivalents of hydrogen are absorbed, the reaction mixture is filtered,evaporated and distilled to give 3.75 (w.) (aldehyde hydrogen), 5.80(s.) (aldehyde max.

carbonyl) NMR: 9.83 (multiplet, aldehyde H), 4.63 (broad singlet) and3.68 (3 proton multiplet, O--C--H protons), 2.57 (diffuse quartet, J =7c.p.s., C-,u protons) p.p.m.

Analysis.-Found (percent): C, 69.31; H, C H O requires (percent): C,69.38; H, 10.81.

(g) 7-(tetrahydropyran 2 yloxy)-2-dodecyn-4-ol. A solution of 60 g. ofpropyne in 800 ml. of THF is added dropwise over 1 hr. to 168 ml. of 3 MEtMgBr/ether with stirring under nitrogen. After bubbling propynethrough the reaction mixture for 15 min., the mixture is cooled to 5 C.with methanol-ice and 82.2 g. of 4-(tetrahydropyran-Z-yloxy)nonanal in150 m1. of THF is added dropwise over /2 hour while maintaining thetemperature at 0 C. After stirring at 0 C. for /2 hour and at 25 C. for2 hours, the mixture is added to 3 liters of saturated NH Cl solutionand extracted with ether. The extract is washed with water, dried,evaporated and distilled to obtain 76.3 g. of product (a viscous oil)B.P. -145 C./0.05 mm.,

A2,; 3.00 (M) (hydroxyl) p.

NMR: 1.72 (broad singlet, propynyl methyl) p.p.m.

Analysis.-Found (percent): C, 72.02; H, 10.91. C H O requires (percent):C, 72.30; H, 10.71.

(h) 2-acetylnonadioic acid, l-t-butyl ester, 9-ethyl ester.t-Butylacetoacetate (14.6 g.) is added dropwise over /2 hour to a stirredmixture of 4.0 g. of 50% NaH- mineral oil in 20 ml. of dimethylformamide and 40 ml. of benzene under nitrogen. After stirring at 25 C.for 1 hour, 10.0 g. of ethyl 7-bromoheptanoate is added and the mixtureis refluxed for /2 hour, then diluted with water and extracted withether. After washing with 5% NaOH and water, the extract is dried,evaporated and the residue chromatographed on silica. Elution with 1:19ether-benzene affords 14.2 g. of product,

MP1; 5.80 (s.) (carbonyls) a NMR: 4.14 (quartet, I =7 c.p.s., ethyl CH3.32 (triplet, J =7 c.p.s., C-2 H), 2.28 (multiplet, C-8 protons), 2.20(singlet, acetyl methyl), 1.47 (singlet, t-butyl protons), 1.25(triplet, J =7 c.p.s., ethyl CH p.p.m.

Analysis.--Found (percent): C, 64.98; C H O requires (percent): C,64.94; H, 9.62.

(i) 7 (tetrahydropyran 2 yloxy) 2 dodecyn-4-ol, methanesulfonate.-Anice-cooled mixture of 19.9 g. of7-(tetrahydropyran-Z-yloxy)-2-dodecyn-4-ol and 8.0 ml. of pyridine istreated with 6.0 ml. of methanesulfonyl chloride and stirred for 15minutes. The resulting viscous suspension is kept at 0 C. for 12 hours,diluted with ether and filtered. The ether solution is Washed thricewith water, once with brine, filtered through Na SO and dried over MgSO,for 2 hours. After filtration and evaporating of the ether at 30 C./ 20mm., the residue is stirred under 0.005 mm. pressure at 25 C. for 2hours to give 23.2 g. of crude7-(tetrahydropyran-Z-yloxy)-2-dodecyn-4-ol, methanesulfonate,

film 4.50 (w.) (0 0), 7.35 and 8.50 (s.) (mesylate) NMR: 5.22 (broadmultiplet, C-4 H), 3.11 (s., mesylate CH 1.92 (doublet, propynyl CHp.p.m. Since the mesylate decomposes to a black tar after 16 hours at 25C., the crude product is immediately used in the next step.

(j) 2-acetyl-2-[l-(l-propynyl) 4 (tetrahydropyram2-yloxy)nonyl]nonanedioic acid, l-t-butyl, 9-ethyl ester.- To a stirredmixture of 3.02 g. of 50% NaH-oil in 6 ml. of benzene and 30 ml. DMFunder nitrogen, 19.8 g. of 2-acetyl-1,9-nonadioic acid, l-t-butyl ester,9-ethyl ester is added dropwise over 15 minutes. After stirring at 25 C.for /2 hour, 22.95 g. of the mesylate of step (i) is added and themixture is refluxed for /2 hour. The cooled reaction mixture is dilutedwith water, extracted with 23 ether and the extract washed with water,dried, and evaporated. Chromatography of the residue on alumina(Activity 3, neutral) and elution with benzene affords 22.3 g. ofproduct, a viscous oil,

REL; 5.80 (s.) (carbonyl) NMR: 4.68 (broad multiplet, OCHO), 4.13(quartet, 1:7 c.p.s., ethyl CH 2.25 (multiplet, C-2 protons and acetylCH 1.77 and 1.80 (propynyl CH 1.48 (s., t-butyl protons), 1.25 (t., 1:7c.p.s., ethyl CH p.p.m.

Analysis.-Found (percent): C, 70.12; H, 10.04. C I-1 requires (percent):C, 70.55; H, 10.10.

(k) 2-acetyl-2-[4 hydroxy 1 (1 propynyl)-nonyl] nonanedioic acid,l-t-butyl, 9-ethyl ester.A solution of 20.2 g. of2-acetyl-2-[1-(l-propynyl)-4-(tetrahydropyran- 2-yl0xy)nonyl]nonanedioicacid, l-tert-butyl 9-ethyl ester in 200 m1. of THF is treated with 70ml. of 6 N HCl and the 2 phase mixture is stirred for 1 hour whilemaintaining the temperature at 25 C. with an ice-bath as necessary. Themixture is diluted with water, extracted with ether and the extractwashed with 5% KHCO water and dried. Evaporation and chromatography ofthe residue on alumina (neutral, Activity 3) followed by elution with1:19 ether-benzene affords 10.9 g. of product, a viscous oil,

A212; 2.90 (M) (hydroxyl), 5.80 (s.) (carbonyl) NMR: 4.13 (q., 1:7c.p.s., ethyl CH 3.66 (broad multiplet, C-12 H), 2.95 (broad multiplet,C-9 H), 2.30 (multiplet, C-2 protons), 2.20 and 2.23 (acetyl CH 1.78 and1.81 (propynyl CH 1.48 (s., t-butyl protons), 1.25 (t., 1:7 c.p.s.,ethyl CH p.p.m.

Analysis.Found (percent): C, 70.30; H, 10.00. C H O requires (percent):C, 70.41; H, 10.19.

(1) Z-acetyl 2 [4-hydroxy-1-(1-propynyl)nonyl]nonanedioic acid,l-t-butyl, 9-ethyl ester, acetate-A solution of 5.3 g. of2-acetyl-2-[4-hydroxy-1-(l-propynyl) nonyl]nonanedioic acid,l-tert-butyl 9-ethyl ester in 50 ml. of pyridine and 6.4 m1. of aceticanhydride is kept at 25 C. for 16 hours. The mixture is diluted withwater, extracted with ether and the extract is washed with 2 N HCl,water and dried. Evaporation of the extract and chromatography of theresidue on alumina (neutral, Activity 3) followed by elution withbenzene affords 3.6 g. of product, a viscous oil,

5.78 (s.) (carbonyl) n NMR: 4.86 (broad multiplet, C-12 H), 4.09 (q.,1:7 c.p.s., ethyl CH 2.85 (broad multiplet, C-9 H), 2.26 (multiplet, C-2protons), 2.16 and 2.18 (acetyl CH 2.00 (s., acetate CH 1.75 and 1.78(propynyl CH 1.45 and 1.47 (t-butyl protons), 1.23 (t., J :7 c.p.s.,ethyl CH Analysis.Found (percent): C, 69.26; H, 9.62. C31H52O7 requires(percent): C, 69.37; H, 9.77.

(m) 2-acetyl-2-[4-hydroxy 1 (1-propeny1)nonyl]nonanedioic acid,l-t-butyl, 9-ethyl ester, acetate.-A solution of 4.1 g. of2-acetyl-2-[4-hydroxyl-1-(l-propynyl) nonylJnonanedioic acid,l-tert-butyl 9-ethyl acetate in 40 ml. of ethyl acetate is added to 0.8g. of 2% Pd/CaCO prehydrogenated in 40 m1. of ethyl acetate and themixture is hydrogenated at 25 C. and atmospheric pressure. After 1equivalent of H is absorbed (20 minutes), the mixture is filtered,evaporated and the residue chromatographed on alumina (neutral, Activity3). Elution with benzene affords 2.7 g. of product, a clear oil,

123;, 5.80 (s.) (carbonyl) NMR: 4.6-5.8 (diffuse multiplet, C-12 H andolefinic protons), 4.10 (q., J:7 c.p.s., ethyl CH 2.97 (broad multiplet,C9 H), 2.26 (multiplet, C-2 protons), 2.14 (s., acetyl CH 2.00 (s.,acetate CH 1.61 and 1.63 (d., 1:6.5 c.p.s., propenyl CH 1.48 (s.,t-butyl protons), 1.23 (t., 1:7 c.p.s., ethyl CH p.p.m.

Analysis.Found (percent): C, 69.20; H, 9.80. C31H5101 requires(percent): C, 69.11; H, 10.10.

(n) 8-acetyl-12-hydroxy-9-(1 propenyl)heptadecanoic acid, ethyl ester,acetate.p-Toluenesulfonic acid (82 mg.) is added to 2.3 g. of2-acetyl-2-[4-hydroxy-1-(1-p1'0- penyl)nonyl] nonanedioic acid,l-tert-butyl, 9-ethyl ester, acetate, stirring under nitrogen at C. andthe mixture is stirred for 1% hour. The cooled mixture is diluted withether, washed with 5% KHCO water and dried. Evaporation andchromatography of the residue on neutral alumina (Activity 3) followedby elution with 1:1 hexanebenzene affords 0.9 g. of the title product, a2:1 mixture of 2 close stereoisomers on TLC and GPC,

A2111, 5.75 (s.) (carbonyl) ,1

NMR: 4.65.8 (diffuse multiplet, C12 and olefinic protons), 4.09 (q., J:7c.p.s., ethyl CH 1.9-2.8 (10 proton multiplet; acetyl CH acetate CH C-2,0-8 and C-9 protons), 1.59 (d., J:7 c.p.s., propenyl CH 1.23 (t., J:7c.p.s., ethyl CH p.p.m.

AnaIysis.-Found (percent): C, 71.22; H, 10.60. C H O requires (percent):C, 71.19; H, 10.57.

(0) 8 acetyl-12-hydroxy-9-(1-propenyl)heptadecanoic acid.The product ofstep (11) (6.9 g.) is stirred at 25 C. for 4.5 hrs. in 100 ml. ofethanol and 100 ml. of 1 N aqueous sodium hydroxide. Dilute the mixturewith water and extract with ether to obtain 6.1 g. of the title compoundNMR: 5.3 (broad multiplet, olefinic proton), 2.07 and 2.15 (singlets,acetyl, CH 1.61 (doublet, J:6 c.p.s., propenyl CH p.p.m.

(p) 8-acetyl-12-hydroxy-9-(1 propenyl)heptadecanoic acid, methylester.The product of step (0) (6.0 g.) is treated with excessdiazomethane in ethyl ether for 1 hr. at 25 C. Decompose the excessdiazomethane with acetic acid, wash the mixture with Water and evaporateto obtain 5.8 g. of the title compound,

NMR: 5.3 (broad multiplet), 3.65 (3 proton singlet, methyl ester), 2.08,2.15 (singlets, acetyl CH 1.60 (doublet, J :6 c.p.s., propenyl CH p.p.m.

(q) 8 acetyl-12-(tetrahydropyran-Z-yloxy)-9-(l-propenyl)heptadecanoicacid, methyl ester.Stir the product of step (p) (5.7 g.) with 50 mg. ofp-toluenesulfonic acid and 3.64 g. of dihydropyran in 53 ml. of benzenefor 20 minutes at 25 C. Dilute the mixture with ether, wash with water,evaporate and chromatograph the residue on neutral alumina to obtain 4.0g. of the title compound,

NMR: 5.3 (broad multiplet, olefinic protons), 3.65 (singlet, methylester), 2.05 and 2.14 (singlets, acetyl CH 1.62 (doublet, 1:5 c.p.s.,propenyl CH p.p.m.

(r) 2-(3-tetrahydropyranyloxyoctyl) 3(6-carbomethoxyhexyl)levulinaldehyde.The product of step (q) (1.8 g.) isozonized in 70 ml. of methylene chloride and 0.32 ml. of pyridine at 70C. until a blue color develops. Treat the cold solution with 2.32 g. ofpowdered zinc and 4.7 ml. of acetic acid. After stirring at 25 C. for 1hr., filter the mixture, dilute the filtrate with ether, wash with waterand evaporate. The resulting residue is dissolved in benzene, filteredthrough alumina and evaporated to obtain 1.5 g. of the title compound,

NMR: 9.55 (multiplet, aldehyde proton), 3.65 (singlet, methyl ester),2.24 and 2.16 (singlets, acetyl CH p.p.m.

(s) 8 acetyl-12-hydroxy-9-(l-propynyl)heptadecanoic acid, ethylester.Stir 9.7 g. of 2-acetyl-2-[1-(1-pro pynyl)-4-(tetrahydropyran2yl0xy)nonyl] nonanedioic acid, 1-tert-butyl-9-ethyl ester [Example 2(1')] under nitrogen at a temperature of C. and add 2.44 g. of

calcium iodide. Continue stirring at 150 for 25 minutes, cool anddissolve the reaction product in ether and water. Separate and wash andether layer with aqueous sodium chloride solution, dry over MgSO, andevaporate. Chromatography of the residue on neutral alumina and elutionwith 1:9 ether-benzene aifords 2.2 g. of the title product,

the following 2,3-disubstituted levulinaldehydes are obtained:

CHz(CHa) aCH CHKCHQMCH;

CH2(CH2)1BC s CH2(CH2)isCHa Y2: 2.9 (hydroxyl), 5.8 (carbonyl), 13.8(double bond) 2, mass spec; I'n./e. 396 (molecular ion).

(u) 8-acety1-9-(1-propenyl 12 (tetrahydropyran-Z- yloxy)heptadecanoicacid, ethyl ester.Treat a solution of 7.2 g. of8-acetyl-12-hydroxy-9-(1-propenyl)heptadecanoic acid, ethyl ester [step(t)] and 4.8 g. of dihydropyran in 125 ml. of benzene with 280 mg. ofp-toluenesulfonic acid and stir at 25 for 20 minutes. Dilute thereaction mixture with ether, wash with water, dry and evaporate.Chromatograph the residue on neutral alumina and elute with 1:1benzene-hexane to obtain 2.8 g. of the title product,

A2,; 5.7 and 5.8 (oarbonyls), 13.7 (double bond) 1.

(v) 8 acetyl 9-(l-propynyl)-12-(tetrahydropyran-2- yloxy)heptadecanoicacid, ethyl ester.Treat a solution of 1.3 g. of 8 acetyl 12hydroxy-9-(1-propynyl)heptadecanoic acid, ethyl ester [step (s)] and0.87 g. of dihydropyran in 25 ml. of benzene with 50 mg. ofp-toluenesulfonic acid and stir at 25 for 20 minutes. Dilute thereaction mixture with ether, wash with water, dry and evaporate toobtain 1.6 g. of the title product,

A213; 5.75 and 5.80 (carbonyls) (w) 8-acetyl-9-(1-propenyl) 12(tetrahydropyran-Z- yloxy)heptadecanoic acid, ethyl ester.--Add asolution of 0.5 g. of 8-acetyl-9-(l-propynyl)-12-(tetrahydropyran-2-yloxy)heptadecanoic acid, ethyl ester [step (v)] in m1. of ethylacetate to 0.1 g. of 10% Pd/charcoal prehydrogenated in 15 ml. of ethylacetate and hydrogenate at 25 and atmospheric pressure until 1equivalent of hydrogen is absorbed. Filter the catalyst and evaporate toobtain at 25 C. for one-half hour, filter the mixture, dilute thefiltrate with ether, wash with water and evaporate. The resultingresidue is dissolved in benzene, filtered through alumina and evaporatedto obtain 1.6 g. of .the title compound,

NMR: 9.6 (multiplet, aldehyde proton), 4.13 (quartet), 2.18 (singlet). 1

EXAMPLE 3 The process of Procedure A is repeated substituting, in step(a), appropriately-substituted starting materials and EXAMPLE 4 4,5-dimethyl-2- cyclopentenl-one Treat a solution of 11.8 g. of2,3-dimethyllevulinaldehyde in 2 liters of water with 220ml. of 5 Nsodium hydroxide and stir for 15 min. at room temperature. Extract themixture with methylene chloride and distill the washed and dried extractto obtain 6.3 g. of the title product, B.P. 5963/ 10 mm.,

h 5.88 1, 6.30;, m, 220 mp. (9,000)

Found (percent): C, 76.52; H, 9.46. Calcd. for C H O (percent): C,76.32; H, 9.15. NMR: 7.59 (1 proton quartet, J =6 and 2.5 c.p.s., C-3H). 6.13 (1 proton quartet, L6 and 2.0 c.p.s., C-2 H), 2.55 (1 protondiifuse multiplet, C4 H), 1.88 (1 proton octet, 1:75 and 2.5 c.p.s., 05H), 1.22 and 1.17 (3 proton doublets, J=7 c.p.s.,

methyl groups) p.p.m.

EXAMPLE 5 4-(3-tetrahydropyranyloxyoctyl)-5-(6'-carboxyhexyl)-2-cyclopenten-1-one and methyl ester thereof Treat a solution of 1.5 g.of 2-(3'-tetrahydropyrany1oxyoctyl)-3-(6-carbomethoxyhexyl)levulinaldehyde (Example 2) in 200 ml.of dioxane and 92 ml. of water with 6.1 m1. of 5 N aqueous sodiumhydroxide and stir the mixture at 25 C. for 0.5 hour. Dilute the mixturewith water, acidify and extract with ether. Evaporate the extract andchromatograph the residue on silica to obtain 1.2 g. of

the title compound,

at; 5.80, 5.88, 6.30,. NMR: 7.58 and 6.12 (multiplets, olefinicprotons), 4.65 and 3.60 (multiplets, O CH protons, 2.33 (triplet, J =7c.p.s., methylene adjacent to carbomyl) p.p.m.

If the reaction is terminated after 3-5 minutes, the methyl ester of thetitle compound is isolated.

EXAMPLE 6 4- (3 -acetoxyoctyl) -5- (6-carboethoxyhexyl -2-cyclopenten-l-one 2 (3'acetoxyoctyl)-3-(6'-carboethoxyhexyl)levulinaldehyde is made up into a0.5% solution by weight in a 0.1 N solution of NaOH in 2:1 dioxane-waterfor 10 minutes at 25 C. The mixture is evaporated to dryness in a vacuumand the residue is extracted with methylene 4- (3'-hydroxyocty1) -5-(6'-carboxyhexy1)-2-cyclopenten-l-one A solution of 0.75 g. of 4(3'-tetrahydropyranyloxyoctyl) 5- (6'-carboxyhexyl)-2-cyclopenten-1-one(Example 5) in 50 ml. of tetrahydrofuran and 50 ml. of 1 N hydrochloricacid is stirred at 25 C. for 0.5 hour. Dilute the mixture with water,extract with ether, evaporate and chromatograph the residue on silica toobtain 0.33 g. of the title compound,

NMR: 7.60 and 6.13 (multiplets, olefinic protons), 3.66 (multiplet, O-CHproton), 2.33 (triplets, J =7 c.p.s., methylene adjacent to carbonyl)p.p.m.

28 obtained. The methyl ester of Example is converted by the procedureof Example to the corresponding methyl ester.

EXAMPLE 12 The procedure of Example '9 is repeated substituting the4,5-disubstituted-2-cyclopenten 1 ones of Example 8 as startingmaterials and the following 4,5-disubstituted- 2,3-epoxycyclopentanonesare obtained:

EXAMPLE 8 The procedure of Example 4 is repeated substituting the2,3-disubstituted levulinaldehydes of Example 3 as starting materials.The following 4,5-disubstituted-Z-cyclopentenl-ones are obtained.

EXAMPLE 13 4,5-dimethyl-3-hydroxycyclopentanone Add 4.6 g. of4,5-dimethyl-2,3-epoxypentanone in 15 ml. of methanol to 2.0 g. of 10%palladized charcoal in EXAMPLE 9 4,5-dimethyl-2,3-epoxycyclopentanonewith 0.2 ml. of hydrogen peroxide and 0.87 ml. of

1 N sodium hydroxide and the mixture stirred at 0 C. for 10 minutes.Acidify the mixture with acetic acid, dilute with water and extract withether to obtain 0.22 g. of the title compound x213, 3.0, 5.85 NMR: 3.72and 3.37 (multiplets, C-2 and C-3 protons), 3.65 (multiplet, C-3 octylproton), 2.33 (triplet, J =7 c.p.s,.

methylene adjacent to carboxyl).

EXAMPLE ll 4- 3'-tetrahydropyranyloxyoctyl -5- 6'-carboxyhexyl2,3-epoxycyclopentanone and methyl ester The procedure of Example 10 isrepeated substituting 4- (3' tetrahydropyranyloxyoctyl)5-(6-carboxyhexyl)-2- cyclopenten-l-one as starting material and theproduct is 40 ml. of methanol and hydrogenate at 25 C. and atmosphericpressure. After an uptake of 1.1 M of hydrogen, filter and distill toobtain 1.4 g. of the product, B.P. 73-75 /0.1 mm.

NMR: 4.10 (1 proton multiplet, C-3H), 3.76 (1 proton singlet, hydroxylproton), 150-3.0 (4 proton complex, 02, C-4, and C-SHs), 1.11 (6 protonmultiplet, methyl groups) p.p.m.

EXAMPLE 14 4-(3'-hydroxyoctyl) 5 -(6'carboxyhexyl)-3-hydroxycyclopentanone and 3-tetrahydropyranyl etherthereof (a) A solution of 200 mg. of 4-(3'-hydroxyoctyl)-5-(6-carboxyhexyl) 2,3 epoxycyclopentanone (Example 10) in 5 ml. ofmethanol is added to mg. of 10% Pd/C in 10 ml. of methanol and 0.1 ml.of saturated aqueous sodium acetate and the mixture hydrogenated at 25C. and atmospheric pressure. Filter, evaporate and chromatograph theresidue on silica to obtain the title compound.

(b) The above reaction is repeated substituting 4-(3-tetrahydropyranyloxy-octyl) 5 (6'carboxyhexyl)-2,3- epoxycyclopentanone(Example 11) as starting material and the resulting product, 4-(3'tetrahydropyranyloxyoctyl)-5-(6'-carboxyhexyl) 3 hydroxycyclopentanone,is hydrolyzed with 0.5 N hydrochloric acid in 50% aqueoustetrahydrofuran at 25 C. for 0.5 hr. to obtain the title compound.

EXAMPLE 15 4-(3'-acetoxyoctyl)-5-(6-carboethoxyhexyl)-3-hydroxycyclopentanone The procedure of Example 14 is repeatedsubstituting 4-(3'-acetoxyoctyl) 5 (6' carboethoxyhexyl) 2,3-epoxycyclopentanone as starting material and the product is obtained.

29 EXAMPLE 16 The procedure of Example =13 is repeated substituting the4,5-disubstituted-2,3-epoxycyclopentanones of Example 12 andcorresponding 2,3-epoxides obtained by entirely analogous processes asstarting materials and the following4,5-disubstituted-3-hydroxycyclopentanones are obtained.

CH3(CH:) (CH CO CHZ (CH2) 40H;

CHzCHzCHlO C CH (GHz)t1CHal (CH2)4CH;

The procedure of Example 13 is repeated, substituting for the palladizedcharcoal catalyst, equivalent amounts of the following catalysts:palladium on carbon, platinium, and unsupported palladium. Substantiallythe same results are obtained.

EXAMPLE 18 The product of Example 4 is separated into its 4,5-cis and4,5-trans isomers by preparative scale gas liquid chromatography using a5 foot column of SE- (a silicone rubber gum) on Chromosorb W (an inertchromatographic support) at a column temperature of 104 C. with nitrogenas a carrier gas at 2 pounds per square inch gauge pressure. Thetrans-isomer is converted to the corresponding 4,5-trans-4,5-dimethyl 3hydroxycyclopentanone by the procedures of Examples 9 and 13.

EXAMPLE 19 (aa) 4-(3' methanesulfonyloxy 1' octenyl) 5 (6'-carboxy-2'-hexenyl)-2-cyclopenten-1-one.Treat an icecooled solution of4-(3'-hydroxy-1-octenyl)-5-(6 carboxy-2-hexenyl) 2 cyclopenten-one inpyridine with one equivalent of methanesulfonyl chloride and keep themixture at 0 for sixteen hours. Add the reaction mixture to water,acidify with hydrochloric acid and extract with ether. After washing theextract with water, dry and evaporate under reduced pressure to obtainthe title product.

(bb) 4-(3'-formyloxy-1'-octenyl) 5 (6'-carboxy-2'-hexenyl)-2-cyclopenten-1-one.-Reflux a solution of 4-(3-methanesulfonyloxy 1' octenyl) 5 (6'-carboxy-2-hexenyl)-2cyclopenten-1-one and four equivalents of tetraethylammoniumformate in acetone for seventeen hours. Remove the acetone under reducedpressure, add water and extract with ether. Wash the extract with water,dry, evaporate and chromatograph the residue on silica gel to obtain thetitle product.

(cc) 4-(3'-hydroxy 1 octenyl) 5 (6'-carboxyl-2'-hexenyl)2,3-epoxycyclopentane.-Treat an ice cooled solution of4-(3-formyloxy-1'-octenyl)-5-(6'-carboxy 2- hexenyl)-2-cyclopenten-1-oneand four equivalents of hy- 4-(3-hydroxy-1'-octenyl) 5(6'-carboxy-2-hexenyl)- 2,3-epoxycyclopentanone to a suspension of 10%Pd/C in methanol containing 1% of saturated aqueous sodium acetatesolution and hydrogenate at 25 and atmospheric pressure until threemolar equivalents of hydrogen are absorbed. Filter, evaporate andchromatograph the residue on silica to obtain the title product. Theidentity of the compound is confirmed by comparing with previouslyproduced compounds of the same formula.

As will be obvious to those skilled in the art, because of centers ofasymmetry, many of the compounds of Formula I prepared by this inventionare capable of being optical isomers. It is a matter of common knowledgeand experience that naturally-occurring prostaglandins and metabolitesthereof are optically-active. The instant total synthesis provides meansto obtain products of Formula I either in racemic or in optically-activeform. In the product of the synthesis which has not included a suitableresolution stage (e.g., by resolving the diastereomeric mixed salt of anoptically-active base with an appropriate acidic intermediate shownherein, or by resolving a diasteromeric mixed ester of a carbinolintermediate shown herein with an optically-active acrylating agent),the compounds of Formula I prepared by the invention will be present asracemates. The optically-active enantiomorphs can be prepared usingoptically-active intermediates or they can be obtained by resolvingracemic products of Formula I by well-known procedures.

We claim:

1. 4-(3' tetrahydropyranyloxyoctyl) 5 (6'-carboxyhexyl)-3-hydroxycyclopentanone.

References Cited UNITED STATES PATENTS 3,435,053 3/1969 Beal et al.260468 D NORMA S. MILESTONE, Primary Examiner US. Cl. X.R.

260345.8, 345.9, 348 C, 405.5, 410.9, 468 D, 483, 488 R, 514 D, 586 R,595, 598, 602, 632 Y, 654, R; 424-317

